Genome-wide Association Research Articles

GenomicSEM Modelling of Diverse Executive Function GWAS Improves Gene Discovery.

Previous research has supported the use of latent variables as the gold-standard in measuring executive function. However, for logistical reasons genome-wide association studies (GWAS) of executive function have largely eschewed latent variables in favour of singular task measures. As low correlations have traditionally been found between individual executive function (EF) tests, it is unclear whether these GWAS have truly been measuring the same construct. In this study, we addressed this question by performing a factor analysis on summary statistics from eleven GWAS of EF taken from five studies, using GenomicSEM. Models demonstrated a bifactor structure consistent with previous research, with factors capturing common EF and working memory- specific variance. Furthermore, the GWAS performed on this model identified 20 new genomic risk loci for common EF and 4 for working memory reaching genome-wide significance beyond what was found in the constituent GWAS, together resulting in 29 newly mapped EF genes. These results help to clarify the underlying genetic structure of EF and support the idea that EF GWAS are capable of measuring genetic variance related to latent EF constructs even when not using factor scores. Furthermore, they demonstrate that GenomicSEM can combine GWAS with divergent and non-ideal measures of the same phenotype to improve statistical power.

Association of genetically predicted levels of circulating blood lipids with coronary artery disease incidence.

Estimating the genetic risk of coronary artery disease (CAD) is now possible by aggregating data from genome-wide association studies (GWAS) into polygenic risk scores (PRS). Combining multiple PRS for specific circulating blood lipids could improve risk prediction. Here, we sought to evaluate the performance of PRS derived from CAD and blood lipids GWAS to predict the incidence of CAD. This study included individuals aged between 40 and 69 from UK Biobank. We conducted GWAS for blood lipids measured by nuclear magnetic resonance in individuals without lipid-lowering treatments (n=73,915). Summary statistics were used to derive PRS in the remaining participants (n=318,051). A PRSCAD was derived using the CARDIoGRAMplusC4D GWAS. Hazard ratios (HR) for CAD (n=9017 out of 301,576; median follow-up: 12.6 years) were calculated per standard deviation increase in each PRS. Models' discrimination capacity and goodness-of-fit were evaluated. Out of 30 PRS, 27 were significantly associated with the incidence of CAD (p<0.0017). The optimal combination of PRS included PRS for CAD, VLDL-C, total cholesterol and triglycerides. Discriminative capacities were significantly increased in the model including PRSCAD and clinical risk factors (CRF) (C-statistic=0.778 [0.773-0.782]) compared to the model with CRF only (C-statistic=0.755 [0.751-0.760], difference=0.022 [0.020-0.025]). Although the C-statistic remained similar when independent lipids PRS were added to the model with PRSCAD and CRF (C-statistic=0.778 [0.773-0.783]), the goodness-of-fit was significantly increased (chi-square test statistic=20.18, p=1.56e-04). Although independently associated with CAD incidence, blood lipids PRS provide modest improvement in the predictive performance when added to PRSCAD.

Genetic association between inflammatory factors and abdominal aortic aneurysm: Insights from a genome-wide association study.

Abdominal aortic aneurysm (AAA) is a fatal vascular disorder. The current primary treatment for AAA remains restricted to surgical intervention during advanced stages of the disease, with no efficacious pharmaceutical options available for early-stage AAA patients. Inflammation is known to play a substantial role in the development of AAA, with various inflammatory factors implicated in its pathogenesis. However, conflicting findings have been reported in studies investigating the roles of these inflammatory factors in AAA, making it challenging to establish definitive causal relationships between inflammatory factors and AAA. The research conducted a bidirectional Mendelian randomization (MR) study using genetic variants. Inflammatory factors were obtained from a genome-wide association study (GWAS), while AAA were sourced from the FinnGen consortium. The primary method employed was inverse-variance weighted (IVW), with MR-Egger, weighted median, and MR-PRESSO approaches used as supplementary analyses. According to the IVW method, hepatocyte growth factor (HGF), matrix metalloproteinase-7 (MMP-7), MMP-12, and NF-kappa-B essential modulator (NEMO/ IKKγ) were associated with a potential increased risk of AAA, while platelet-derived growth factor BB (PDGFbb), interleukin-4 (IL-4), IL-12p70, IL-10, IL-6Rα, and myeloperoxidase (MPO) were associated with a potential decreased risk of AAA. In the reverse MR analysis, no causal relationship was observed between AAA and any of the inflammatory factors. This study provides evidence supporting a causal relationship between inflammatory factors and AAA. It suggests that targeting and modulating these specific inflammatory factors may serve as a potential approach for the prevention and noninvasive treatment of AAA.

Genome-wide association mapping and genomic prediction analyses reveal the genetic architecture of grain yield and agronomic traits under drought and optimum conditions in maize

BackgroundDrought is a major abiotic stress in sub-Saharan Africa, impacting maize growth and development leading to severe yield loss. Drought tolerance is a complex trait regulated by multiple genes, making direct grain yield selection ineffective. To dissect the genetic architecture of grain yield and flowering traits under drought stress, a genome-wide association study (GWAS) was conducted on a panel of 236 maize lines testcrossed and evaluated under managed drought and optimal growing conditions in multiple environments using seven multi-locus GWAS models (mrMLM, FASTmrMLM, FASTmrEMMA, pLARmEB, pKWmEB, ISIS EM-BLASSO, and FARMCPU) from mrMLM and GAPIT R packages. Genomic prediction with RR-BLUP model was applied on BLUEs across locations under optimum and drought conditions.ResultsA total of 172 stable and reliable quantitative trait nucleotides (QTNs) were identified, of which 77 are associated with GY, AD, SD, ASI, PH, EH, EPO and EPP under drought and 95 are linked to GY, AD, SD, ASI, PH, EH, EPO and EPP under optimal conditions. Among these QTNs, 17 QTNs explained over 10% of the phenotypic variation (R2 ≥ 10%). Furthermore, 43 candidate genes were discovered and annotated. Two major candidate genes, Zm00001eb041070 closely associated with grain yield near peak QTN, qGY_DS1.1 (S1_216149215) and Zm00001eb364110 closely related to anthesis-silking interval near peak QTN, qASI_DS8.2 (S8_167256316) were identified, encoding AP2-EREBP transcription factor 60 and TCP-transcription factor 20, respectively under drought stress. Haplo-pheno analysis identified superior haplotypes for qGY_DS1.1 (S1_216149215) associated with the higher grain yield under drought stress. Genomic prediction revealed moderate to high prediction accuracies under optimum and drought conditions.ConclusionThe lines carrying superior haplotypes can be used as potential donors in improving grain yield under drought stress. Integration of genomic selection with GWAS results leads not only to an increase in the prediction accuracy but also to validate the function of the identified candidate genes as well increase in the accumulation of favorable alleles with minor and major effects in elite breeding lines. This study provides valuable insight into the genetic architecture of grain yield and secondary traits under drought stress.

Integration of GWAS models and GS reveals the genetic architecture of ear shank in maize.

Maize is one of the most important crops for human food, animal feed, and industrial raw materials. Ear shank length (ESL) and ear shank node number (ESNN) are crucial selection criteria in maize breeding, impacting grain yield and dehydration rate during mechanical harvesting. To unravel the genetic basis of ESL and ESNN in maize, an association panel consisting of 379 multi-parent doubled-haploid (DH) lines was developed for genome-wide association studies (GWAS) and genomic selection (GS). The heritabilities of ESL and ESNN were 0.68 and 0.55, respectively, which were controlled by genetic factors and genotype-environment interaction factors. Using five different models for GWAS, 11 significant single nucleotide polymorphisms (SNPs) located on chromosomes 1, 2, and 4 were identified for ESL, with the phenotypic variation explained (PVE) value of each single SNP ranging from 4.91% to 21.35%, and 11 significant SNPs located on chromosomes 1, 2, 4, and 5 were identified for ESNN, with the PVE value of each SNP ranging from 1.22% to 18.42%. Genetic regions in bins 1.06, 2.06, and 2.08 were significantly enriched in SNPs associated with ear shank-related traits. The GS prediction accuracy using all markers by the five-fold cross-validation method for ESL and ESNN was 0.39 and 0.37, respectively, which was significantly improved by using only 500-1000 significant SNPs with the lowest P-values. The optimal training population size (TPS) and marker density (MD) for ear shank-related traits were 50%-60% and 3000, respectively. Our results provide new insights into the GS of ear shank-related traits.

Genetics of constant and severe pain in the NAPS2 cohort of recurrent acute and chronic pancreatitis patients.

Recurrent acute and chronic pancreatitis (RAP, CP) are complex, progressive inflammatory diseases with variable pain experiences impacting patient function and quality of life. The genetic variants and pain pathways in patients contributing to most severe pain experiences are unknown. We used previously genotyped individuals with RAP/CP from the North American Pancreatitis Study II (NAPS2) of European Ancestry for nested genome-wide associated study (GWAS) for pain-severity, chronicity, or both. Lead variants from GWAS were determined using FUMA. Loci with p<1e-5 were identified for post-hoc candidate identification. Transcriptome-wide association studies (TWAS) identified loci in cis and trans to the lead variants. Serum from phenotyped individuals with CP from the PROspective Evaluation of Chronic Pancreatitis for EpidEmiologic and Translational StuDies (PROCEED) was assessed for BDNF levels using Meso Scale Discovery Immunoassay. We identified four pain systems defined by candidate genes: 1) Pancreas-associated injury/stress mitigation genes include: REG gene cluster, CTRC, NEURL3 and HSF22. 2) Neural development and axon guidance tracing genes include: SNPO, RGMA, MAML1 and DOK6 (part of the RET complex). 3) Genes linked to psychiatric stress disorders include TMEM65, RBFOX1, and ZNF385D. 4) Genes in the dorsal horn pain-modulating BDNF/neuropathic pathway included SYNPR, NTF3 and RBFOX1. In an independent cohort BDNF was significantly elevated in patients with constant-severe pain. Extension and expansion of this exploratory study may identify pathway- and mechanism-dependent targets for individualized pain treatments in CP patients. PERSPECTIVE: Pain is the most distressing and debilitating feature of chronic pancreatitis. Yet many patients with chronic pancreatitis have little or no pain. The North American Pancreatitis Study II (NAPS2) includes over 1250 pancreatitis patients of all progressive stages with all clinical and phenotypic characteristics carefully recorded. Pain did not correlate well with disease stage, inflammation, fibrosis or other features. Here we spit the patients into groups with the most severe pain and/or chronic pain syndromes and compared them genetically with patients reporting mild or minimal pain. Although some genetic variants associated with pain were expressed in cells (1) of the pancreas, most genetic variants were linked to genes expressed in the nervous system cells associated with (2) neural development and axon guidance (as needed for the descending inhibition pathway), (3) psychiatric stress disorders, and (4) cells regulating sensory nerves associated with BDNF and neuropathic pain. Similar and overlapping genetic variants in systems 2 -4 are also seen in pain syndromes form other organs. The implications for treating pancreatic pain are great in that we can no longer focus on just the pancreas. Furthermore, new treatments designed for pain disorders in other tissues may be effective in some patient with pain syndromes from the pancreas. Further research is needed to replicate and extend these observations so that new, genetics-guided rational treatments can be developed and delivered.

Overview of the etiology of childhood cancer and future directions.

We provide an overview of the etiology of childhood cancer, the state of the literature, and highlight some opportunities for future research, including technological advancements that could be applied to etiologic studies of childhood cancer to accelerate our understanding. Risk factors of childhood cancer were summarized based on demographics and perinatal factors, environmental risk factors, and genetic risk factors. Overall, demographics and perinatal factors are the most well studied in relation to childhood cancer. While environmental risk factors have been implicated, more work is needed to pinpoint specific exposures, identify window(s) of susceptibility, and understand mechanisms. With genome-wide association studies (GWAS), genetic risk factors of eight childhood cancers have emerged, and opportunities remain to conduct GWAS for other cancer types and determine whether risk variants are inherited or de novo. Technological advancements that can shed light into the susceptibility of childhood cancer include metabolomics, using primary teeth as an exposure matrix, and long-read sequencing. The development of childhood cancer remains largely not well understood. Collaboration to increase sample size to conduct analyses by histology and/or molecular subtype and application of novel technologies will accelerate our understanding of childhood cancer.

A multi-trait approach identified 7 novel genes for back pain.

Back pain (BP) is a complex heritable trait with an estimated heritability of 40% to 60%. Less than half of this can be explained by known genetic variants identified in genome-wide association studies. We applied a powerful multi-trait and gene-based approach to association analysis of BP to identify novel genes associated with BP. Using phenotypes and imputed genotypes from the UK Biobank 500k dataset, we generated a multi-trait phenotype by combining 3 BP-related phenotypes: chronic BP, dorsalgia, and intervertebral disk disorders. We performed gene-based association analysis for 3 BP-related phenotypes and multi-trait phenotype. Conditional analysis was applied to account for the effects of genetic variants outside the gene. Finally, we replicated significantly associated genes using the FinnGen database. We identified 32 genes associated with BP and replicated 16 of them. Thirteen genes were detected using the multi-trait phenotype. Seven of the detected genes, MIPOL1, PTPRC, RHOA, MAML3, JADE2, MLLT10, and RERG, were not previously reported. Several new genes are known to be associated with traits genetically correlated with BP or to be involved in pathways associated with BP. Using new powerful methods of association analysis, we identified 7 novel genes associated with BP. Our results provide new insights into the genetics of back pain.

Association of organ iron levels with type 2 diabetes mellitus and glycemic traits: A bidirectional two-sample Mendelian randomization study.

Observational studies have found that higher iron levels are associated with an increased risk of diabetes mellitus. Given the limitations of causal inferences from observational studies and the expensive and time-consuming nature of randomized controlled trials, Mendelian randomization analysis presents a reasonable alternative to study causal relationships. Previous MR analyses studying iron levels and diabetes have used indirect markers of iron levels, such as serum ferritin, and found conflicting results. In this study, we performed bidirectional Mendelian Randomization analyses using organ iron (liver, spleen, and pancreas) levels, which are more direct markers of iron status, to study the causal association of iron levels with type 2 diabetes mellitus and glycaemic traits. Two sample MR analyses were employed bi-directionally to study the causal effect of liver, spleen, and pancreas iron levels on type 2 diabetes and glycaemic traits and the causal effect of type 2 diabetes on organ iron levels, using summary data from genome-wide association studies (UK-Biobank, DIAGRAM, and MAGIC consortia). SNPs associated with organ iron levels with a cut-off of P < 5 × 10-7 were used as instrumental variables for the MR analyses of the effect of organ iron levels on type 2 diabetes/glycaemic traits, and SNPs associated with diabetes mellitus with a cut-off of P < 5 × 10-8 were used as instrumental variables for the MR analyses of the causal effect of type 2 diabetes on organ iron levels. Serum ferritin (GWAS meta-analysis of deCODE, UK INTERVAL, and Denmark studies) and haemoglobin (Blood Cell consortium) were used as positive controls for the MR analysis with liver iron as the exposure. Primary analyses used the inverse variance weighted means of Wald's ratio. Sensitivity analyses included inverse variance weighted median, weighted mode, and MR-Egger methods. Our findings reveal no causal association between liver and pancreas iron levels with type 2 diabetes (Liver iron: OR = 1.02, P = 0.1, Pancreas iron: OR = 1.11, P = 0.5). This also holds for glycaemic traits, except for the negative causal effect of liver iron levels on HbA1c (OR = 0.93, P = 0.001). Spleen iron levels had a negative causal effect on type 2 diabetes (OR = 0.94, P = 0.049). However, these exceptions are likely due to possible pleiotropy, as these associations can be explained by the effect of the genetic variants on factors that falsely decrease HbA1c levels. No causal association was found for the effect of type 2 diabetes on organ iron levels. Organ iron levels, which are relatively more direct indicators of iron status, showed no causal association with type 2 diabetes in the European population.

Modifiable lifestyle factors and risk of intracranial aneurysm: A univariate and multivariate Mendelian randomisation study.

The aim of this study was to assess the potential causal relationship between lifestyle factors and intracranial aneurysms (IAs) using a two-sample Mendelian randomization (MR) approach. The study used a pooled dataset from a genome-wide association study that covered information on 24 lifestyle factors, intracranial aneurysm cases, subarachnoid hemorrhage, and unruptured aneurysms. Five MR methods were applied for analysis by selecting single nucleotide polymorphisms as instrumental variables, with the inverse variance weighting method as the main method. To ensure the stability of the results, horizontal multiple validity tests, sensitivity analyses, and inverse MR were performed, and genetically determined exposure factors were adjusted by multivariate MR. Several lifestyle factors were found to have a significant genetic causal effect on the occurrence and development of intracranial aneurysms. For example, lamb intake, smoking initiation, number of cigarettes smoked per day, length of television viewing, and fatigue were identified as genetic risk factors and strongly associated with aneurysm rupture, whereas red wine intake showed some genetic protection against intracranial aneurysms and similarly affected aneurysm rupture. Sensitivity analyses and inverse MR verified the robustness of these results. After adjusting for exposure factors, multivariate MR confirmed daily smoking and smoking initiation as risk factors for intracranial aneurysms, unruptured aneurysms, and subarachnoid hemorrhage, whereas red wine intake was a genetically protective factor against intracranial aneurysms and subarachnoid hemorrhage. This MR analysis revealed a genetic causal link between specific lifestyle factors and intracranial aneurysms, emphasizing the need for further studies to confirm these findings and explore their mechanisms.

Development and application of a cGPS 20K liquid-phase SNP microarray in Jiaji ducks.

In order to provide a low-cost, high efficient, and highly accurate tool for molecular breeding of Jiaji ducks, we constructed a cGPS(Genotyping by Pinpoint Sequencing of captured targets) 20 K liquid-phase microarray using resequencing data from this valuable poultry breed for the first time. The microarray contains 20,327 high-quality snp loci, mainly from the 30 Jiaji duck resequencing samples collected in this study, and some loci were supplemented from the 135 duck resequencing data from KUNMING INSTITUTE OF ZOOLOGY.CAS. This microarray showed excellent performance in two production tests. The microarray was used to genotype a population of 236 Jiaji ducks, and the genotyping data were then used for population structure analysis and genome-wide association studies (GWAS) of plumage color phenotypes. According to the population structure analysis, the population of Jiaji ducks could be divided into four subpopulations using genetic distance matrices. Using GWAS analysis, 38 significant SNP loci were identified within a region on chromosome 14 that contained 30 genes. Among them, EDNRB2 and VAMP7 were identified as strong candidate genes for the regulation of plumage color in Jiaji ducks. Two mutations upstream of EDNRB2 were identified as tightly linked to the colorless phenotype. In addition, two KASP markers were designed for the SNP loci associated with EDNRB2 (HIC_SCAFFOLD_14_14984620, HIC_SCAFFOLD_14_15016766). The KASP genotyping results showed strong correlations between different genotypes on the SNP locus HIC_SCAFFOLD_14_15016766 and the plumage phenotype. In conclusion, this independently designed microarray will be useful for large-scale genotyping and can lay the foundation for future screening of mutation loci and functional genes.

Copper and iron as unique trace elements linked to fibromyalgia risk.

Fibromyalgia (FM) is a prevalent chronic pain condition with a complex and not fully understood etiology. Abnormal metabolism of trace elements is suspected to play a role in the pathogenesis of FM, though the exact relationships have yet to be clarified. This study employed Mendelian randomization (MR) to assess potential causal relationships between 15 major trace elements and the risk of FM, focusing on the specific roles of elements that show significant associations. Genetic instrumental variables (single nucleotide polymorphisms, SNPs), related to these trace elements and FM were extracted from genome-wide association studies (GWAS). Analyses were performed using various methods including inverse-variance weighting (IVW), MR Egger, weighted median, weighted mode, and simple mode. Furthermore, multivariable analysis controlled for selenium as a potential confounder to evaluate the independent associations of copper (Cu) and iron (Fe) with FM risk. Two-sample MR analysis indicated a positive association between Cu and increased risk of FM (IVW: OR = 1.095, 95% CI: 1.015 to 1.181, P = 0.018), and a negative association between Fe and FM risk (IVW: OR = 0.440, 95% CI: 0.233 to 0.834, P = 0.011). These associations remained significant in the multivariable analysis, highlighting the independent effects of Cu and Fe. No significant correlations were observed with other trace elements such as selenium and zinc. This study provides new evidence of the roles of Cu and Fe in the pathophysiology of FM and underscores the importance of considering trace elements in the prevention and treatment strategies for FM. Future research should further validate these findings and explore the specific biological mechanisms through which Cu and Fe influence FM risk.

Several variants on chromosome 10 are associated with coarse hair diameter in Dazu black goats (Capra hircus).

Goats typically have double coats, with the outermost coarse hairs providing protection against mechanical and radiation damage. While much attention has been paid to cashmere due to its status as a high-end textile material, there is limited information available on coarse hair. This study aimed to identify genomic variants, such as single nucleotide polymorphisms (SNPs) and insertion/deletions (indels), associated with coarse hair diameter using a genome-wide association study (GWAS). Coarse hairs and blood samples were collected from 263 adult female goats. The diameter of coarse hairs was measured using an inverted microscope, and whole genome sequencing was conducted on the blood samples. After reads mapping, variants calling, and quality control, totals of 11 322 006 SNPs and 863 734 indels were included for SNP-GWAS and indel-GWAS analyses. Eight significant SNPs (p < 8.98e-8) and three significant indels (p < 1.16e-6) were identified. Among those, one SNP was located on Chromosome 4 and near the genes COL28A1 and C1GALT1. Seven significant SNPs were found in the region chr10_96664101-96670958, with the genes CDO1 and TMED7 located upstream and downstream, respectively. Haplotype analysis revealed that the diverse haplotypes of these seven SNPs presented varying values for coarse hair diameter. Notably, the only consistently significant insertion (chr10_96665085, GTA>G) was also located within the region chr10_96664101-96670958, further highlighting the importance of this genomic region in influencing coarse hair diameter. These significant variants and genomic regions provide valuable insights for investigating the genetic mechanisms underlying the variation in fiber diameter.

Exploring the role of inflammatory biomarkers in trigeminal neuralgia.

Trigeminal neuralgia (TN) is a severe facial pain disorder with complex etiology. Inflammation has been suggested as a contributing factor to TN pathogenesis. This study investigates the causal relationship between inflammatory biomarkers, including 41 circulating inflammatory cytokines, C-reactive protein (CRP), and procalcitonin (PCT), and TN using Mendelian randomization (MR) analysis. A two-sample MR approach was employed using genome-wide association study (GWAS) data from 8293 Finnish individuals for inflammatory cytokines and data from the FinnGen database for TN. Instrumental variables (IVs) were selected based on genome-wide significance and clumping thresholds to avoid linkage disequilibrium. Inverse variance weighting (IVW) was used as the primary method, complemented by MR Egger regression, weighted median, simple mode, and weighted mode methods. Additionally, Bayesian Weighted MR (BWMR) and Multivariable MR (MVMR) were utilized to validate the findings and explore potential confounders. The present MR analysis identified significant causal associations for three inflammatory cytokines with TN. Stem cell growth factor beta (SCGF-β) (OR=1.362, 95% CI=1.049-1.770, p=0.021) and Interleukin-4 (IL-4) (OR=1.533, 95% CI=1.014-2.316, p=0.043) were positively associated with TN, while Interleukin-16 (IL-16) (OR=0.720, 95% CI=0.563-0.921, p=0.009) had a protective effect. CRP levels were also linked to TN risk (OR=0.751, 95% CI=0.593-0.951, p=0.017). No significant causal effect of PCT on TN was observed. Sensitivity analyses confirmed the robustness of these findings, showing no evidence of horizontal pleiotropy or heterogeneity. This study highlights specific inflammatory biomarkers that may play pivotal roles in TN pathogenesis. SCGF-β and IL-4 are potential therapeutic targets due to their facilitative effects on TN, while IL-16 could offer protective benefits. CRP's association with TN further supports the involvement of systemic inflammation in this condition. These findings provide novel insights into TN's inflammatory mechanisms, suggesting new avenues for targeted interventions.

Deciphering resistance to Tomato brown rugose fruit virus (ToBRFV) using Genome-Wide Association Studies

Deciphering resistance to Tomato brown rugose fruit virus (ToBRFV) using Genome-Wide Association Studies

Association between chronic obstructive pulmonary disease and osteoporosis: Mendelian randomization combined with bibliometric analysis

BackgroundPrevious observational studies have reported an association between chronic obstructive pulmonary disease (COPD) and osteoporosis (OP). The aim of this study is to investigate the causal relationship between COPD and OP by two-sample Mendelian randomization (MR) analysis. The current status of cross-sectional research between COPD and OP in the past decade was explored through bibliometrics.MethodsSingle nucleotide polymorphisms (SNPs) that have been found to be strongly associated with COPD were used as instrumental variables (IVs) in MR Analysis. The primary outcome of the study was BMD measurement at five specific anatomical sites, namely the whole body, femoral neck, lumbar spine, forearm, and heel. These BMD measurements were derived primarily from a genome-wide association study (GWAS) and summary statistics from the International Genetic Factors Consortium for Osteoporosis (GEFOS). The main analysis method was inverse variance weighting (IVW). Multiple sensitivity analyses were performed to assess the robustness and reliability of the current MR Results. Further confirmatory MR Analysis between COPD and OP was applied. In bibliometrics. Publications were extracted from the Web of Science core collection publications related to osteoporosis and sarcopenia published between January 2014 and October 2024; Bibliometrics and visualization were performed by Microsoft Office Excel, Citespace, and R (Bibliometrix).ResultsThe MR Findings suggest that there is no causal relationship between COPD and BMD at five specific anatomical sites. The results of the primary IVW MR Analysis were generally supported by our sensitivity MR Analysis. We performed MR Analysis for the validation of COPD and OP (IVW OR: 1.019; 95%CI: 0.898–1.564; p = 0.768) also did not support a causal relationship between COPD and BMD. A total of 471 articles written by 1119 organizations from 42 countries/regions by 3331 authors and published in 238 journals were identified in the bibliometric analysis. China is the leading country in terms of the number of publications. China Medical University contributed the most publications. The International Journal of Chronic Obstructive Pulmonary Disease has the highest publication in this field.ConclusionsIn conclusion, This MR Study found no causal relationship between COPD and OP, suggesting that the observed associations may be due to common genetic effects or environmental confounders. The global research trends in this field in the past decade were summarized through bibliometric analysis, and care became the focus of future research on the relationship between copd and OP.

Shared chemoresistance genes in ESCC and cervical Cancer: Insights from pharmacogenomics and Mendelian randomization.

Neoadjuvant chemotherapy, particularly the use of platinum-based compounds and taxanes, is pivotal in the treatment of epithelial-derived tumors, such as cervical cancer and esophageal squamous cell carcinoma (ESCC); however, resistance remains a significant challenge. Utilizing Mendelian randomization (MR) with pharmacogenomics offers a novel approach to understanding the genetic underpinnings of drug responses, thereby aiding in personalized treatment. Single-cell RNA sequencing (scRNA-seq) analysis revealed a shared cellular subpopulation of CD8+T effector memory (CD8+TEM) cells that are pivotal in mediating chemotherapy resistance in ESCC and cervical cancer. A two-sample approach was employed for MR using data from genome-wide association studies, focusing on single nucleotide polymorphisms (SNPs) linked to CD8+TEM cell expression. The SNPs were carefully selected, and statistical models, including the Wald ratio and inverse variance weighted methods, were used for robust causal effect estimation. These were supplemented by MR-Egger and weighted median analyses to address pleiotropy and variant heterogeneity. 3-(4,5-Dimethylthiazol-2-yl)-2,5 diphenyl tetrazolium bromide (MTT) and immunohistochemistry assays were used to verify the relationship between the gene and drug sensitivity. Increased proportion of CD8+TEM cells were observed in resistant samples. MR identified IL32, SPOCK1, and TRBC2 as key genes associated with resistance to cisplatin, carboplatin, and paclitaxel, respectively. These findings were validated across various cohorts and underscored the role of CD8+TEM cells in drug responsiveness. The results of the MTT and immunohistochemistry assays confirmed the MR findings. Our study highlights the significant role of CD8+TEM cells in the chemoresistance of ESCC and cervical cancer and identified three genetic markers crucial for resistance to common chemotherapeutic agents. These findings suggest potential pathways for developing personalized treatment strategies, offering clinically relevant insights that could enhance therapeutic efficacy and help overcome drug resistance in patients with ESCC or cervical cancer.

The Spectrum of Genetic Risk in Alzheimer Disease.

Alzheimer disease (AD), the most common dementing syndrome in the United States, is currently established by the presence of amyloid-β and tau protein biomarkers in the setting of clinical cognitive impairment. These straightforward diagnostic parameters belie an immense complexity of genetic architecture underlying risk and presentation in AD. In this review, we provide a focused overview of the current state of AD genetics. We discuss the discovery of familial autosomal dominant genes, the identification of candidate genes associated with AD, and genetic variants conferring higher risk of developing AD compared with the general population. In particular, we discuss important features of AD risk due to the APOE ε4 allele. In addition to risk, we describe how the field has made headway understanding genetic factors that may protect from AD. The biological implications and practical limitations of information gleaned from genome-wide association studies in AD over the years are also discussed. The readers will have an up-to-date understanding of where we are in our efforts to understand the layers of genetic complexity in AD.

Mendelian randomization and mediation examination of the immune cell-mediated link between sphingomyelin and stroke.

The study established a direct link between stroke and sphingomyelin. The precise biology underlying this connection is yet unknown, though. As a result, we decided to investigate the potential causal relationship between Sphingomyelin and genetic vulnerability to stroke, as well as the potential mediating function that immune cells may play in this process, using Mendelian randomization (MR) approaches. A published genome-wide association study (GWAS) dataset of European populations served as the foundation for the MR Study. The inverse variance weighting (IVW) model is the main technique. Four additional statistical techniques (MR Egger, Weighted median, Simple mode, and Weighted mode) were also employed to enhance the verification process. Reverse MR Analysis was utilized to reinforce the findings, and heterogeneity and horizontal pleipotency were assessed. Additionally, this study looked into potential immune cell mediating roles in the causal link between sphingomyelin and stroke using two-step MR techniques. The IVW metod's results indicated that sphingomyelin genetic susceptibility was linked to a high risk of stroke (OR = 1.045 [95%CI, 1.004-1.087; P = 0.031). Additionally, the statistical result of SSC-A on CD8br and stroke was IVW [P = 0.007, OR(95% CI) 1.020 (1.005-1.034)], which was proportionate to the increased risk of stroke. A lower incidence of stroke IVW is linked to CD45 on CD8br [P=0.004, OR(95% CI) 0.993 (0.988-0.998)]. Furthermore, our results imply that SSC-A on CD8br and CD45 on CD8br contribute to the causative relationship between sphingomyelin and stroke. The percentages of conciliation are 5.38%, 22.7%, 33.5%), and 0.000999, 0.0152, 0.0132, respectively. We confirmed the effect of sphingomyelin on stroke and conducted in-depth studies. SSC-A on CD8br and CD45 on CD8br is latent stroke mediators associated with sphingomyelin. Through two-step mediated Mendelian randomization analysis, we provide new insights into the etiology and treatment of stroke.

Unraveling the impact of blood RANKL and OPG levels on Alzheimer's disease: Independent of bone mineral density and inflammation.

Observational studies have revealed a close relationship between reduced bone mineral density (BMD) and Alzheimer's disease (AD) risk. The receptor activator of nuclear factor kappa-B ligand (RANKL) and osteoprotegerin (OPG) system, pivotal in regulating bone metabolism, has been implicated in brain function, but the causal impact on AD risk remains unclear. We employed bi-directional Mendelian randomization (MR) and multivariable MR (MVMR) approaches to elucidate the effect of blood soluble RANKL (sRANKL) and OPG levels on AD, assessing whether this influence was independent of BMD and inflammation. Three distinct AD genome-wide association study (GWAS) data sets from the International Genomics of Alzheimer's Project (IGAP), UK Biobank (UKB), and FinnGen were utilized. Summary-level data on blood sRANKL and OPG were sourced from deCODE Genetics. Genetically predicted per standard deviation (SD) increase in blood sRANKL levels was significantly associated with a reduced risk of AD across all three AD GWAS data sets (IGAP: odds ratio [OR]=0.82, 95% confidence interval [CI]=0.72-0.94, p=0.004; UKB: OR=0.85, 95% CI=0.78-0.91, p < 0.001; FinnGen: OR=0.83, 95% CI = 0.73-0.94, p=0.004). No significant causal relationship was observed between OPG levels and AD. In addition, there was no causal impact of AD on the blood levels of sRANKL and OPG. MVMR results showed that the inverse association between sRANKL and AD risk persisted after adjusting for BMD and interleukin-1α and chemoattractant protein-1. Our study provides evidence that elevated sRANKL levels are causally linked to a reduced risk of AD, independent of BMD and inflammation. These findings enhance our understanding of the complex interactions between bone metabolism and AD. Blood soluble receptor activator of nuclear factor kappa-B ligand (sRANKL) levels are linked to a reduced risk of Alzheimer's disease (AD).The association between sRANKL levels and AD is independent of bone mineral density (BMD) and inflammation.No causal link exists between blood osteoprotegerin levels and AD.AD does not affect blood levels of sRANKL or osteoprotegerin.